Background: Neonatal deaths account for over 40% of all under-5 year deaths; their reduction is increasingly critical for achieving Millennium Development Goal 4. An estimated 3 million newborns die annually during their first month of life; half of these deaths occur during delivery or within 24 hours. Every year, 6 million babies require help to breathe immediately after birth. Resuscitation training to help babies breathe and prevent/manage birth asphyxia is not routine in low-middle income facility settings. Helping Babies Breathe (HBB), a simulation-training program for babies wherever they are born, was developed for use in low-middle income countries. We evaluated whether HBB training of facility birth attendants reduces perinatal mortality in the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Global Network research sites. Methods/design: We hypothesize that a two-year prospective pre-post study to evaluate the impact of a facility-based training package, including HBB and essential newborn care, will reduce all perinatal mortality (fresh stillbirth or neonatal death prior to 7 days) among the Global Network’s Maternal Neonatal Health Registry births ≥1500 grams in the study clusters served by the facilities. We will also evaluate the effectiveness of the HBB training program changing on facility-based perinatal mortality and resuscitation practices. Seventy-one health facilities serving 52 geographically-defined study clusters in Belgaum and Nagpur, India, and Eldoret, Kenya, and 30,000 women will be included. Primary outcome data will be collected by staff not involved in the HBB intervention. Additional data on resuscitations, resuscitation debriefings, death audits, quality monitoring and improvement will be collected. HBB training will include training of MTs, facility level birth attendants, and quality monitoring and improvement activities. Discussion: Our study will evaluate the effect of a HBB/ENC training and quality monitoring and improvement package on perinatal mortality using a large multicenter design and approach in 71 resource-limited health facilities, leveraging an existing birth registry to provide neonatal outcomes through day 7. The study will provide the evidence base, lessons learned, and best practices that will be essential to guiding future policy and investment in neonatal resuscitation. Trial registration: Trial registration ClinicalTrials.gov Identifier: NCT01681017